ABSTRACT This is an initial application for a U01 in response to PAR-15-067. This program announcement grew out of an NIDDK Workshop held in 2013 to identify pathways for promoting research on fecal incontinence (FI). Conference attendees identified gaps in knowledge and the best approaches to progress, and all identified Biofeedback (BIO), Sacral Neural Stimulation (SNS), and Injections of bulking agents (INJ) in the perianal space as treatments supported by controlled trials, but with no clear indication of which is most effective, safest, and least costly. Outcome measures have been variable, and inclusion criteria have also differed. The recommendation was to compare all 3 using the same paradigm. Aims: (1) Compare all 3 treatments on the basis of efficacy, safety, and cost, as well as secondary outcome measures. (2) Identify physiological, clinical, and psychosocial predictors of who will respond to each treatment. (3) Allow patients who do not respond to the randomly assigned treatment to select a second treatment at 3 months. (4) Compare treatment combinations to see which appears best (uncontrolled). (5) Assess the effects of enhanced Medical Management (MM) on efficacy, safety, and cost (uncontrolled). (6) Compare the cost-effectiveness of BIO, SNS, and INJ for FI throughout the two years. Methods: Select 567 patients appropriate to all treatments including >2 per week solid or liquid FI. A treatment responder is someone with >75% reduction in FI frequency. Primary assessment is 3 months after the beginning of randomized treatment. If patients are responders, they will continue to be studied for 24 months, but if they fail to respond they will be offered alternative treatment and followed. Secondary outcomes include the rate of responding with a 50% decrease in FI, continence, changes on the Bristol Stool Severity scale, FI Quality of Life, and validated severity scales (FI Severity Scale, St. Mark?s FI Severity Scale). Psychological outcomes include the PROMIS Anxiety-7, Depression-8, and Self-Efficacy scales. Costs effectiveness analysis will be based on Quality Adjusted Life Years. Moderators will include (1) physiological assessments (anal ultrasound, anorectal motility, and magnetic evoked potentials); (2) a priori beliefs in treatments (Credibility/Expectancy Questionnaire), quality of life (general and FI specific), sex, and type of FI (passive, urge). The 4 clinical site principal investigators (PIs) are Adil Bharucha (Mayo Clinic), Satish Rao (University of Augusta in Georgia), Ann Lowry (Colon and Rectal Surgery in Minneapolis), and William Whitehead (Chapel Hill, NC) ? all senior PIs. The PI of the data coordinating center (DCC) is Marie Gantz, also an experienced PI. This is a collaborative agreement with NIDDK, and Frank Hamilton will participate in program management. A successful outcome will guide treatment algorithms and reimbursement policies.